The present invention teaches the synthesis of chlorinated racemic heterocyclic compounds. Purified enantiomers of chlorinated heterocyclic compounds, and the synthesis of the same, are also taught in the present invention.
A variety of heterocyclic compounds have been described as having various pharmaceutical applications. However, the synthesis of such compounds, especially on a large scale, is often labor-intensive, expensive and time consuming. For compounds with a chiral center (i.e. compounds which have enantiomers), it is often desirable to be able to obtain a composition which is significantly enriched for one enantiomer over another enantiomer of the same compound, as enantiomers, while identical with respect to certain physical properties, such as melting and boiling points, may differ in their chemical, biological or biochemical properties.
In view of the different chemical, biological or biochemical properties associated with different enantiomers, chemists have explored many approaches for acquiring enantiomerically pure compounds including the resolution of the racemates using chiral stationary phases, structural modifications of naturally occurring chiral substances (as reagents for running stereospecific reactions) and asymmetric catalysis using chiral catalysts or enzymes.
Optically active catalysts or enzymes have limited application in multiple step and kilo scale processes due to their high prices. Similarly the use of chiral stationary phases, for optical resolution, is a very expensive means for kilo scale production.
What is needed, therefore, is a simplified and economical method for the stereospecific synthesis of heterocyclic compounds and acquisition of purified enantiomers for those compounds with chiral centers.
The present invention relates to heterocyclic compositions and methods for their synthesis. The compositions comprise a racemic mixture of monochloroflosequinan, and derivatives (e.g. the sulfone) thereof. Other compositions comprise enantiomers of monochloroflosequinan. The compositions also comprise chlorodesoxyflosequinan.
In one embodiment, the present invention contemplates compositions comprising racemic monochloroflosequinan (i.e. racemic 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another embodiment, the present invention contemplates compositions comprising the sulfone derivative of racemic monochloroflosequinan (i.e. 3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone). In one embodiment, the present invention contemplates compositions comprising a purified enantiomer of monochloroflosequinan, including derivatives thereof. In one embodiment, said purified enantiomer of monochloroflosequinan is a (+)-enantiomer (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another embodiment, said composition is substantially free of the (xe2x88x92)-enantiomer of monochloroflosequinan. In yet another embodiment, said purified enantiomer of monochloroflosequinan is a (xe2x88x92)-enantiomer (i.e. (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone). In another embodiment, said composition is substantially free of the (+)-enantiomer of monochloroflosequinan.
In some embodiments, a composition comprising a substantially purified enantiomer of monochloroflosequinan is contemplated. In some embodiments, the purified enantiomer (i.e. the (+)- or the (xe2x88x92)-enantiomer of monochloroflosequinan) represents at least 80% of the purified enantiomer preparation, more preferably at least 90%, more preferably at least 95% and even more preferably, at least 98% of the preparation. Likewise, the other enantiomer represents less than 20%, 10%, 5% or 2% of the preparation.
In some embodiments, a composition comprising an enantiomer of monochloroflosequinan (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone or (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) in enantiomeric excess is contemplated. In some embodiments, the major enantiomer in the composition is in at least 90% enantiomeric excess, and more preferably, 95% enantiomeric excess. In some embodiments, a composition comprising (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 85% is contemplated. In other embodiments, a composition comprising (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 95% is contemplated. In other embodiments, a composition comprising (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 85% is contemplated. In yet other embodiments, a composition comprising (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone having an optical purity of at least 95% is contemplated.
In one embodiment, the present invention contemplates compositions comprising chlorodesoxyflosequinan (i.e. 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone).
In one embodiment, the present invention contemplates methods for the synthesis of racemic monochloroflosequinan. In another embodiment, the present invention contemplates methods for the synthesis of the sulfone derivative of racemic monochloroflosequinan. In yet other embodiments, the present invention contemplates methods for the stereopreferred synthesis (e.g. the preferential synthesis of one enantiomer) and separation of enantiomers of monochloroflosequinan. In one embodiment, a method for the synthesis of the (+)- enantiomer of monochloroflosequinan (i.e. (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) in enantiomeric excess is contemplated. The method further provides additional separation steps. In another embodiment, a method for the synthesis of the (xe2x88x92)-enantiomer of monochloroflosequinan (i.e. (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) in enantiomeric excess is contemplated. The method further provides additional separation steps. In some embodiments, the present invention provides methods of synthesis of chlorodesoxyflosequinan (i.e. 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone).
In some embodiments, the present invention provides a method, comprising: a) providing: i) flosequinan, and ii) triphenyl phosphine; and b) reacting said flosequinan and triphenyl phosphine in an organic solvent under conditions such that desoxyflosequinan (7-fluoro-1-methyl-3-methylthio-4-quinolone) is produced; and c) further reacting said desoxyflosequinan with N-chlorosuccinimide and 2,2xe2x80x2-azobisisobutyronitrile in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced. A variety of solvents can be used in this reaction. In some embodiments, said organic solvent in said reacting step b) is selected from the group consisting of carbon tetrachloride, xylene and toluene. In some embodiments, said providing step a) optionally provides iii) a catalyst, and said reacting step b) occurs in the presence of said catalyst. In some embodiments, said organic solvent in said reacting step b) is selected from the group consisting of xylene and toluene. A variety of solvents can be used in this reaction. A variety of catalysts are contemplated for this reaction. In some embodiments, said catalyst is tetrabromomethane. In some embodiments, said organic solvent in step c) is selected from the group consisting of carbon tetrachloride and benzene.
In another embodiment, the present invention provides a method, comprising:
a) providing: i) flosequinan, ii) thionyl chloride, and iii) pyridine; and b) reacting said flosequinan, thionyl chloride and pyridine in an organic solvent under conditions such that chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone) is produced.
In another embodiment, the present invention provides a method, comprising:
a) providing: i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), ii) hydrogen peroxide, and iii) potassium carbonate; and b) reacting said chlorodesoxyflosequinan, hydrogen peroxide and potassium carbonate in a solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced.
In yet other embodiments, the present invention provides a method, comprising:
a) providing: i) flosequinan, and ii) N-chlorosuccinimide; and b) reacting said flosequinan and N-chlorosuccinimide in an organic solvent under conditions such that monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone) is produced. A variety of solvents are contemplated. In some embodiments, said organic solvent is selected from the group consisting of carbon tetrachloride and benzene. In other embodiments, when said organic solvent is carbon tetrachloride, said reacting step b) additionally includes 2,2xe2x80x2-azobisisobutyronitrile.
In another embodiment, the present invention provides a method, comprising:
a) providing: i) chlorodesoxyflosequinan (3-chloromethylthio-7-fluoro-1-methyl-4-quinolone), and ii) a camphor based reagent; and b) reacting said chlorodesoxyflosequinan and camphor based reagent in an organic solvent under conditions such that an enantiomer of monochloroflosequinan is produced in enantiomeric excess. In some embodiments said camphor based reagent is (R)-(xe2x88x92)-(10-camphorsulfonyl) oxaziridine. In such embodiments, said enantiomer of monochloroflosequinan is (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. In yet other embodiments, said camphor based reagent is (S)-(+)-(10-camphorsulfonyl) oxaziridine. In such embodiments, said enantiomer of monochloroflosequinan is (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone.
In some embodiments, a one-step method of synthesis of 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is contemplated. The method comprises: a) providing: i) flosequinan, and ii) N-chlorosuccinimide; and b) reacting, in an organic solvent, said flosequinan with said N-chlorosuccinimide under conditions such that 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced. A variety of solvents are contemplated. In some embodiments, said organic solvent is selected from the group consisting of carbon tetrachloride and benzene. In embodiments wherein the solvent is carbon tetrachloride, the reaction additionally includes 2,2xe2x80x2-azobisisobutyronitrile (AIBN).
In other embodiments, a three-step method of synthesis of 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is contemplated. The method comprises: a) providing: i) racemic flosequinan, and ii) triphenyl phosphine; and b) reacting said racemic flosequinan and said triphenylphosphine in an organic solvent under conditions such that 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced; and c) further reacting said 7-fluoro-1-methyl-3-methylthio-4-quinolone with N-chlorosuccinimide and 2,2xe2x80x2-azobisisobutyronitrile in an organic solvent under conditions such that 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is produced; and d) reacting said 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone with hydrogen peroxide under conditions such that 3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced. A variety of solvents are contemplated. In some embodiments, the solvent in step b) is carbon tetrachloride. In some embodiments, the solvent in step c) is carbon tetrachloride. In some embodiments, potassium carbonate is included in said reacting step d).
In other embodiments, alternative methods for the synthesis of 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone are contemplated. In one embodiment, the method comprises: a) providing: i) racemic flosequinan, ii) thionyl chloride, and iii) pyridine; and b) reacting said racemic flosequinan, thionyl chloride and pyridine under conditions such that 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is produced.
In yet other embodiments, methods for the synthesis of the sulfone derivative of monochloroflosequinan are contemplated. In one embodiment, the method comprises: a) providing: i) monochloroflosequinan (3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone), and ii) m-chloroperoxybenzoic acid; and b) reacting said monochloroflosequinan and said m-chloroperoxybenzoic acid under conditions such that monochloroflosequinan sulfone (3-chloromethylsulfonyl-7-fluoro-1-methyl-4-quinolone) is produced.
In other embodiments, 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is used in stereopreferred oxidation reactions to produce (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone or (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. The mixture of enantiomers produced may then be subjected to further separation procedures. In one embodiment, the 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone used in the subsequent synthesis and separation of enantiomers of monochloroflosequinan is synthesized by a method comprising: a) providing: i) racemic flosequinan, ii) triphenylphosphine, and iii) a catalyst; and b) reacting, in a solvent, said racemic flosequinan and said triphenylphosphine in the presence of said catalyst under conditions such that 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced; and c) further reacting said 7-fluoro-1-methyl-3-methylthio-4-quinolone in a solvent with N-chlorosuccinimide and 2,2xe2x80x2-azobisisobutyronitrile under conditions such that 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone is produced. Again, a variety of solvents are contemplated. In some embodiments, said solvent in step b) is toluene and said catalyst is tetrabromomethane (CBr4).
In some embodiments, the method further provides the synthesis of (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. The method further comprises d) reacting said 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone with (S)-(+)-(10-camphorsulfonyl)oxaziridine under conditions such that (R)-(xe2x88x92)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced in enantiomeric excess.
In other embodiments, the method further provides the synthesis of (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone. The method further comprises d) reacting said 3-chloromethylthio-7-fluoro-1-methyl-4-quinolone with (R)-(xe2x88x92)-(10-camphorsulfonyl)oxaziridine under conditions such that (S)-(+)-3-chloromethylsulfinyl-7-fluoro-1-methyl-4-quinolone is produced in enantiomeric excess.
In some embodiments, racemic flosequinan is reacted with triphenyl phosphine and a catalyst in anhydrous xylene to produce 7-fluoro-1-methyl-3-methylthio-4-quinolone. In some embodiments, the catalyst is tetrabromomethane (CBr4). Thus, in one embodiment, a method of synthesis of 7-fluoro-1-methyl-3-methylthio-4-quinolone is provided, comprising: a) providing: i) racemic flosequinan, ii) anhydrous xylene, iii) a catalyst, and iv) triphenyl phosphine; and b) reacting said racemic flosequinan and said triphenyl phosphine in said anhydrous xylene in the presence of said catalyst under conditions such that 7-fluoro-1-methyl-3-methylthio-4-quinolone is produced. In one embodiment, said catalyst is tetrabromomethane (CBr4).